Recent data suggest that the NMDA receptor, a subtype of glutamate receptors, may provide a new avenue of pharmacological intervention for stimulant abuse. Pretreatment with NMDA antagonists in laboratory animals has been shown to block cocaine-induced stereotypy and locomotor activity, and to prevent sensitizaton to the locomotor and reinforcing effects of cocaine. Noncompetive NMDA antagonists inhibit the excitatory glutamate neurotransmitter system by blocking the NMDA-associated calcium channel. In addition, these antagonist have been shown to affect dopaminergic transmission, inhibiting cocaine-induced increases in extracellular dopamine in the nucleus accumbens. If the cocaine-induced increase in dopamine in the nucleus accumbens plays a role in the reinforcing effects of cocaine, these findings suggest that noncompetitive NMDA antagonists may reduce cocaine's reinforcing effects in humans. Furthermore, given the recent investigations showing that these agents prevent the development of opioid tolerance and dependence and may actually attenuate tolerance, NMDA antagonists may prove especially useful for those who are addicted to both cocaine and opioids. To date, we have studied an intriguing NMDA antagonist, memantine, in this laboratory with results which suggest that it may not be useful as a treatment agent for cocaine dependence. We now propose to study amantadine (Symmetrel), the anti-Parkinsonian agent and a derivative of memantine. Amantadine has been somewhat promisisng in open clinical trials with cocaine-dependent individuals. Furthermore, it has a long history in this country of safe use in patients with Parkinson's disease and with various psychiatric disorders. Finally, we have been asked by NIDA to study amantadine in our laboratory, because several groups have found it useful with cocaine addicts. These factors make amantadine a suitable medication for study in our laboratory, and the results obtained will be compared to those we have obtained with memantine.